Substituted esters of benzoic acid



Patented Apr. 20, 1948 means I SUBSTITUTED nsrsas or nsszorc ACID Samuel M. McElvain, Madison, Win, and Thomas ll. Carney, Indianapolis, Ind.

No Drawing. Application April 2?, 1946, Serial N0. 6853M s illlaims. (or. act-ass) This is a continuation-in-part of-our GDDlication Serial No.'602,657, filed June 30, 1945, and which became abandoned August 30, 1946.

This invention relates to anesthetic chemical compositions and is directed to novel substituted;

benzolc acid esters and salts thereof, and compositions containing such esters and their salts.

By this invention there areprovided novel compounds represented by the following formula:

compounds represented above, such as the hydrochloride, hydrobromide, sulfate and phosphate, are white crystalline compounds which are readily water-soluble. Other acid addition salts, for example the picrate and the methylene-bishydroxynaphthoate are stable, crystalline compounds with relatively low water-solubility. Still other acid addition salts such as the oleate are soluble in oils.

Illustrative of the salts of the novel compounds represented above, the hydrochloric acid addition salt of 3-(2'-methylpiperidino) -propyl p-cyclohexyloxybenzoate may be represented by the following formula:

The new compounds of this invention may be prepared by esterification'methods. Thus for example, 3-(2'-methy1piperidino) -propyl -p-cyclohexyloxybenzoate may beprepared in the form of its hydrohalide salt by reacting, Preferably in an inert solvent, a p-cyclohexyloxybenzoyl halide with 3 (2' methylpiperidinol-propyl alcohol.

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Additionally, it may be prepared as a hydrohalide salt by'reacting p-cyclohexyloxybenzoic acid with a 3-(2'-methylpiperidino) -propyl halide in a solvent such as isopropanol. For use in the above methods, the halide of choice is the chloride and when such halide is used, 3-(2'-methylpiperldino) -propyl p-cyclohexyloxybenzoate is isolated as the hydrochloric acid salt. From the hydrochloride thus prepared the free ester may be prepared by treatment with alkali. 3-(2'-methylpiperidino-propyi p-cyclopentyloxybenzoate is prepared in a similar manner.

Acid addition salts of the compounds of this invention may be prepared by treating the ester with the appropriate acid. Furthermore, one salt may be converted to a different salt by treatment with the appropriate acid and preferential crystallization.

Compounds of the present invention have been found to be highly useful in therapeutics. Thus for example, 3-(2'-methylpiperidino)-propy1 pcyclohexyloxybenzoate is readily absorbed by mucous membranes producing an eirective'anesthesia of long duration. Furthermore, it is surprislngly well absorbed by scarified, abraded or burned skin and confers thereon a highly; efiective anesthesia of long duration, without irritation or toxic manifestations even when used over large areas, and the profundity of anesthesia is such'as to permit necessary debridement without discomfort on the part of the patient.

Therapeutic compositions provided by this invention comprise thenovel benzoic acid esters or salts thereof, in association with a, suitable carrier or extending medium, or another therapeutic agent. By incorporation of the esters or salts thereof with such carrier or extending medium,

the anesthetic properties of the novel compounds are utilized to the greatest advantage. The extending medium may be a single compound such as water or oil, or may comprise a multiplicity of compounds some of which in themselves may possess therapeutic properties. Thus the novel esters or salts may be utilized in the form of aqueous solutions which may be isotonic, or as oil solutions or in combination with oil-soluble olntments or water-soluble jellies. Desirably the novel benzoic acid ester or salt thereof is incorporated in the extending medium in relatively minor proportion.

spacers A. Aqueous solution Percent Y D Prldino)-propyl p cyelo- D ntyloxybenmate hydrochloride---" 0.5 Ringer's solution 99.5

B. Oil solution Percent 3-(2-methyipiperidino) -propyl p-cyclohexyloxybenzoate hydrochloride 1.0 Cottonseed oil 99.0

C. Oil-soluble ointment Percent 3- (2'-methylpiperidino) -propyl p-cyclohexyloxybenzoate hydrochloride 1.0 Beeswax 8.0 Cholesterol 1.0 Lanolin 15.0 Stearyl a h 3.0 Petrolatum 71.5 Benzoin 0.5

D. Water-soluble jelly Percent 13- (2'-methylpiperidlno) -propyl p-cyclohexyloxybenzoate hydrochloride 0.5 Glycerin 15.0 Gum tragacanth 2.0 Trisodium phosphate 0.055

Water q. s..- 100.0

Specific examples illustrating the preparation of the novel compounds of this invention are as follows:

Example 1 3-(2'-methylpiperidino) propyl p-cyclohexyloxybenzoate hydrochloride may be prepared as follows:

7.4 of sodium are dissolved in 250 cc. of isoamy1 alcohol, 53 g. of ethyl p-hydroxybenzoate are added and the mixture is heated to refluxin temperature for about 15 minutes. To the cooled mixture, 65 g. of cyclohexyl bromide are added and the mixture is refluxed for about 3 hours. The isoamyl alcohol is removed by evaporation in vacuo and the residue is extracted with 10 percent aqueous sodium hydroxide solution to remove the unreacted ethyl p-hydroxybenzoate. The alkali-insoluble residue comprising ethyl p-cyclohexyloxybenzoate is hydrolyzed by refluxing with 10 percent sodium hydroxide solution for about 3 hours. The alkaline reaction mixture is acidified with hydrochloric acid whereupon p-cyclohexyloxybenzolc acid precipitates. The precipitate is separated by filtration, washed with water and dried. It melts at about PIS-180 0. Yield: about '7 percent.

62 g. of p-cyclohexyloxybenzoic acid and 49.5 e. of 3-(2'-methylplperidino) -propy1 chloride are dissolved in 300 cc. of dry isopropanol and the mixture refluxed for about 12 hours. About half of the isopropanol is then distilled on. and the residual solution cooled to about C. 3(2'-methylpiperidino) propyl p cyclohexyloxybenzoate hydrochloride precipitates as a white crystalline compound. It is filtered off, washed once with ether and recrystallized from isopropanol.

3(2-methylpiperidlno) propyl p cyclohexyloxybenzoate hydrochloride thus prepared melted at about 178-480 C. Analysis showed the presence of 8.88 percent chlorine as compared with the calculated value of 8.06 percent.

Example 2 v 3-(2'-methylpiperidino) propyl p-cyclohexyloxybenzoate may be prepared as follows:

3.8 8. of 3-(2'-metlwlpiperldlno) -propyl p-cyclohexyloxybenzoate hydrochloride are dissolved in 50 cc. of water and to the solution is added a solution of 0.4 g. of sodium hydroxide in 10 cc. of water. The oily 3-(2'-methylpiperidlno)-propyl p-cyclohexyloxybenzoate which separates is taken up in ether, the ether solution separated and dried with potassium carbonate, and the ether evaporated, preferably under vacuum, leaving the 3- (2'-methylpiperldino) propyl p-cyclohexyloxybenzoate as a residual colorless oil which may be further purified bydistillation under reduced pressure.

Example 3 3-(2'-methylpiperidino) propyl p-cyclohexyloxybenzoate hydrochloride may also be prepared in the following manner:

p-Cyclohexyloxybenzoyl chloride is prepared by treating 44 g. of p-cyclohexyloxybenzoic acid with 30 g. of thionyl chloride and refluxing the mixture for about 2 hours. The excess thionyl chloride is removed by evaporation in vacuo leaving the p-cyclohexyloxybenzoyl chloride as an oil.

To a refluxing solution of 12 g. of 3-(2'methylpiperidino) -propyl alcohol dissolved in '70 cc. of dry benzene are added 17 g. of p-cyclohexyloxybenzoyl chloride over a period of about one half hour. The solution is refluxed for a period of about two hours after the p-cyclohexyloxybenzoyl chloride addition has been completed, and is then cooled. The 3 (2' methylplperidino) propyl p cyclohexyloxybenzoate hydrochloride which is formed during the reaction is filtered oil and washed with ether. It is further purified by recrystallization from isopropanol. The 3- 2-.

methylpiperidino) propyl p cyclohexyloxybenzoate hydrochloride melts at about 178-180" C.

Example 4 methylpiperidino) propyl p cyclohexyloxybenzoate hydrochloride.

3-(2'-methylpiperidino) -propyl p-cyclopentyloxybenzoate hydrochloride thus prepared melted at -178" C. Analysis showed the presence of 9.38 percent chlorine as compared with the calculated value of 9.28 percent.

Example 5 3-(2'-methylpiperidino) -propyl p-cyclopentyloxybenzoate may be prepared from the corresponding hydrochloric acid salt by the method described in Example 2 for the preparation of 3-(2'-methylpiperidino) -propyl p-cyclohexyloxybenzoate. 3-(2'-methylpiperldino) -propyl p-cyclopentyloxybenzoate is a colorless oil which may be distilled under reduced pressure.

5 6 Example 5 ggggtllaleanzoate hydrochloride represented by the 3-(2'-methylpiperidino) -propy1 p-cyclopentylv CH oxybenzoate hydrochloride may also be prepared m H, g a from p-cyclopentyloxybenzoic acid by the meth- 5 H-om 3-(2'-methylpiperidino)-propyl p-cyclohexyloxy- C CH g benzoate hydrochloride. m H, n r

3-(2'-methylpiperidino)-propy1 p-cyclopentyloxybenzoate hydrochloride thus prepared melts 1o 3'(z"methylplperidm) "P P'CWIWBR- 0 0d described in Example 3 for the preparation or mc CH0- -0(OHi):-N \H,

at about "5478c tyloxybenzoate represented by the formula It may be noted that the compounds 0! this CH invention also may be prepared by processes of n, trans-esteriflcatio condensation and replacef, 5: meat. I m CH0-C0(C Iz)zN CH2 We claim: Q

1. Novel compounds represented by the tormula n, H:

r i and its acid addition salts. A f v E m 5. Therapeutic compositions comprising a (CH|).CH0C0(CH:)sN on. member 0! the class consisting of compounds V g represented by the formula l- I where n is one of the integers 4 and 5; and acid addition salts thereof. Jim-on.

2. 3-(2'-methylpiperidino)-propyl p-cyclohex- 25 yloxybenzoate represented by the following V H formula cm wherein n is one of the integers 4 and 5, and acid L g addition salts thereof; in association with an I H tendiri di hC\' cn-ol1-O-(0Ih)=-N cm 8 me om-ofi. SAMUEL. M. McELvAm.

THOMAS P. CARNEY. ind its acid addition salts. v

3. 3-(2-methylpiperidino) -propyl p-cyclohex- 

